Movement Disorders are neurological conditions characterized by either a paucity or lack of movement (such as Parkinson disease) or excessive movement (such as dystonia, dyskinesia, tremor, chorea, ballism, akathisia, athetosis, bradykinesia, freezing, rigidity, postural instability, myoclonus, and tics or Tourette syndrome). See, Watts and William eds. (1997); and Shulman and Weiner (1997).
Parkinson's Disease and Motor Complication
Parkinson's disease (paralysis agitans) is a disorder of the brain characterized by shaking and difficulty with walking, movement, and coordination. The disease is associated with damage to a part of the brain that controls muscle movement.
Parkinson's disease was first described in England in 1817 by James Parkinson. The disease affects approximately 2 out of 1,000 people, and most often develops after age 50. The symptoms first appear, on average, at about age 60, and the severity of Parkinson's symptoms tends to worsen over time. It affects both men and women and is one of the most common neurologic disorders of the elderly. The term “parkinsonism” refers to any condition that involves a combination of the types of changes in movement seen in Parkinson's disease. Parkinsonism may be genetic, or caused by other disorders or by external factors (secondary parkinsonism).
In the United States, about a million people are believed to suffer from Parkinson's disease, and about 50,000 new cases are reported every year. Because the symptoms typically appear later in life, these figures are expected to grow as the average age of the population increases over the next several decades. The disorder is most frequent among people in their 70s and 80s, and appears to be slightly more common in men than in women.
The dopaminergic neurons of the substantia nigra pars compacta and ventral tegmental area play a crucial role in regulating movement and cognition, respectively. Several lines of evidence suggest that the degeneration of dopaminergic cells (i.e. dopamine-producing cells) in the substantia nigra produces the symptoms of Parkinson's disease. Dopaminergic cells, concentrated in the region of the substantia nigra, are the fastest aging cells in the body. As dopaminergic cells decay, control over movement is diminished and Parkinson's disease develops.
Usually the first symptom of Parkinson's disease is tremor (trembling or shaking) of a limb, especially when the body is at rest. The tremor often begins on one side of the body, frequently in one hand. Other common symptoms include other movement disorders such as slow movement (bradykinesia), an inability to move (akinesia), rigid limbs, a shuffling gait, and a stooped posture. Parkinson's disease patients often show reduced facial expression and speak in a soft voice. The disease can cause secondary symptoms of depression, anxiety, personality changes, cognitive impairment, dementia, sleep disturbances, speech impairments or sexual difficulties. There is no known cure for Parkinson's disease. Treatment is aimed at controlling the symptoms. Medications control symptoms primarily by controlling the imbalance between the neurotransmitters. Most early Parkinson's disease patients respond well to symptomatic treatment with dopamine replacement therapy, but disability increases with progression of the disease.
The medications used, the dose and the amount of time between doses vary, depending on the case. The combination of medications used may need to be adjusted as symptoms change. Many of the medications can cause severe side effects, so monitoring and follow-up by the health care provider is important.
Although currently available medications for Parkinson's disease generally provide adequate symptomatic control for a number of years, many patients develop motor fluctuations and dyskinesias that compromise clinical response. Rascol et al. (2000); and Parkinson Study Group (2000). Once this occurs, increasing dopaminergic therapy is likely to worsen dyskinesias and decreasing dopaminergic therapy is likely to worsen motor function and increase OFF time. In light of this problem, attention has turned to potential therapeutic manipulation of non-dopaminergic neurotransmitter systems.
Most Parkinson's disease symptoms arise from a deficiency of dopamine and most anti-Parkinson drugs restore dopamine or mimic dopamine's actions. However, the drugs do not permanently restore dopamine or exactly mimic dopamine's actions. While a loss of dopamine cells in the substantia nigra is the main feature of Parkinson's disease, non-dopamine nerve cells are also lost. Moreover, dopamine-responsive cells are present not only in the substantia nigra but in other brain regions. Thus drugs that are effective in Parkinson's disease can, by stimulating these cells, cause side effects such as nausea, hallucinations, and confusion.
In 1967, L-DOPA was introduced and remains the most effective anti-Parkinson drug. Symptoms most likely to benefit from L-DOPA include bradykinesia, rigidity, resting tremor, difficulty walking, and micrographia. Symptoms least likely to benefit from L-DOPA include postural instability, action tremor, and difficulty swallowing. L-DOPA may worsen dementia. Although L-DOPA provides robust and rapid therapeutic benefits in Parkinson's disease, eventually, severe adverse reactions to dopamine emerge, including motor complications such as wearing off phenomenon, ON-OFF fluctuations, and dyskinesia. Marsden et al. (1982). Once established, motor complications are not typically controllable with manipulation of L-DOPA or other dopaminergic drugs.
Early in Parkinson's disease L-DOPA is taken 3 times per day. Peak concentrations in the brain occur 1 to 2 hours after administrations. Although the drug has a short half-life (0.5 to 1 hour) there are sufficient remaining dopamine cells in the brain to store dopamine and maintain its activity over several hours. As Parkinson's disease progresses, more dopamine cells die and the remaining cells cannot store sufficient dopamine to maintain its benefits: the duration of action of each dose decreases and patients need higher or more frequent doses. After 2-5 years as many as 50-75% of patients experience fluctuations in their response to L-DOPA: ON/OFF periods. Associated with the fluctuations, patients develop dyskinesias. The dyskinesias usually occur at the peak effect of L-DOPA but can also occur as the drug wears off, or at stressful times. The fluctuations and dyskinesias can seriously impact the patient's life. If L-DOPA is given continuously (through an intravenous pump) ON/OFF effects disappear and dyskinesias decrease. However, it is impractical to give L-DOPA intravenously.
When L-DOPA is taken alone part of it is changed outside the brain to dopamine by dopa-decarboxylase. The dopamine so produced cannot enter the brain and causes side effects such as nausea, vomiting, and appetite loss. Therefore L-DOPA is often combined with carbidopa or benserazide. Carbidopa blocks dopa-decarboxylase outside the brain allowing more L-DOPA to enter the brain without causing nausea, vomiting, and appetite loss. Atamet or Sinemet are tablets containing both carbidopa and L-DOPA. In combination with carbidopa, the half-life of L-DOPA is 1.2 to 2.3 hours.
Thirty years after its discovery, L-DOPA is still the best treatment for Parkinson's disease. In the early stages of the disease, patients usually enjoy a good response to L-DOPA, but as the disease progresses L-DOPA tends to become less helpful. This is not due to loss of L-DOPA efficacy, but rather to development of motor complications such as adverse fluctuations in motor response including end-of-dose deterioration, or “wearing-off”, and the “ON/OFF” fluctuations and dyskinesias. ON/OFF fluctuations are a sudden, unacceptable loss of therapeutic benefit of a medication (‘ON’ state, during which the patient is relatively free from the symptoms of Parkinson's disease) and onset of the parkinsonian state (‘OFF’ state). Wearing off phenomenon is a decrease in the duration of L-DOPA action, and characterized by the gradual reappearance of the ‘off’ state, and shortening the ‘on’ state. Dyskinesia can be broadly classified as chorea (hyperkinetic, purposeless dance-like movements) and dystonia (sustained, abnormal muscle contractions). In 1974, Duvoisin first focused on these abnormal involuntary movements, and found that over half of patients with Parkinson's disease developed dyskinesia within six months of treatment. With increasing duration of treatment, there is an increase in both the frequency and severity of dyskinesia. In a seminal study of the potential benefits of possible neuroprotectants in Parkinson's disease—the DATATOP trial—L-DOPA induced dyskinesia was observed in 20-30% of patients who received L-DOPA treatment for a mean of 20.5 months. Ultimately, most L-DOPA treated patients experienced dyskinesia; up to 80% of patients developed dyskinesia within five years of treatment. Parkinson Study Group (1996); and Rascol et al. (2000). Treatment-related dyskinesias are not solely a problem of L-DOPA, as dopamine receptor agonists are also capable of eliciting dyskinesia. Thus, the common term “L-DOPA-induced dyskinesia” could be used to describe dopamine-treatment-related dyskinesia in general terms. Most dyskinesias occur when levodopa or other dopamine receptor agonists have a concentration in the brain that is sufficient to overactive dopamine receptors in the putamen (peak-dose-dyskinesia). However, dyskinesia also occurs when dopamine concentration is low (OFF dystonia) or in stages when the concentration of dopamine rises or falls (biphasic dyskinesia). Other movement disorders, such as myoclonus and akathisia, might also be components of the L-DOPA induced dyskinesia spectrum.
The biological basis of L-DOPA motor complications in Parkinson's disease is still far from clear. It has been suggested that they may involve not only advancing disease and continued loss of nigral neurons, but also changes of dopamine receptor sensitivity and their downstream expression of proteins, and genes, the sequence of events of which relate, at least in part, to the dose and method of administration of L-DOPA or dopamine agonists. Changes in non dopamine systems such as glutamate-mediated neurotransmission, GABA-mediated neurotransmission, and opioid peptide mediated transmission, might also be involved in the neuronal mechanisms that underlie L-DOPA motor complications in Parkinson's disease. Bezard et al. (2001). Notably, it seems that the short plasma half-life and consequent short duration of action of dopaminergic agents and the pulsatile stimulation of dopamine receptors by dopaminergic agents are associated with motor fluctuations and peak-dose-dyskinesias. All these events combine to produce alterations in the firing patterns that signal between the basal ganglia and the cortex.
Originally introduced as adjunctive therapy to L-DOPA in patients with fluctuations, dopamine agonists are now increasingly proposed as monotherapy in early patients. The antiparkinsonian effects of dopamine agonists, however, are usually less than those of L-DOPA, and after two to four years their efficacy wanes. When more potent treatment is required, low doses of L-DOPA can be “added on” to the agonist. An alternative strategy is to combine an agonist with low doses of L-DOPA from the beginning. Both strategies are purported to be as effective as L-DOPA and to have the advantage of significantly reducing the risk of motor fluctuations and dyskinesias. These claims, however, are based upon a small number of pilot studies, all of which suffer from methodological shortcomings.
Additionally, dopamine receptor agonists are also capable of eliciting dyskinesia. Dopamine agonists also provoke dyskinesia in parkinsonian animals previously exposed by L-DOPA. Neuropsychiatric side effects, especially hallucination and psychosis, often limit the use of dopamine agonists. Despite the potential benefits provided by the adjunctive use of dopamine agonists, L-DOPA motor complications can thus be extremely difficult or even impossible to control. See, Olanow, Watts and Koller eds. (2001). Finally, dopamine agonists are sometimes used in monotherapy as substitutes for L-DOPA in patients with advanced Parkinson's disease and severe motor fluctuations and dyskinesias.
More recently, catecholamine-O-methyltransferase (COMT) inhibitors such as tolcapone and entacapone have been proposed as adjunctive therapy to L-DOPA. These compounds extend the plasma half-life of L-DOPA, without significantly increasing Cmax. Thus, they decrease the duration of wearing-off but tend to increase the intensity of peak-dose side effects including peak-dose-dyskinesias. Tolcapone appears to induce significant liver toxicity in a small percentage of patients.
Anti-cholinergics such as tri-hexiphenidyl (Artane) and piperidine (Cogentin) block the actions of acetylcholine in the brain. This may result in a mild to moderate degree of improvement in symptoms such as drooling and tremor. Patients above age 65 are likely to experience side effects such as dry mouth, blurred vision, constipation, confusion and hallucinations when treated with anti-cholinergics.
Dystonias
The term dystonia refers to a movement disorder characterized by sustained muscle contractions resulting in a persistently abnormal posture. Based on this definition, there are a number of dystonic syndromes, which can be subdivided according to their clinical features as: generalized (affecting all body parts); segmental (affecting adjacent body parts); or focal (restricted to a single body part). Focal dystonias include spasmodic torticollis, blepharospasm, hemifacial spasm, oromandibular dystonia, spasmodic dysphonia, and dystonic writer's cramp.
There are several degrees of dystonia. Some people can maintain a relatively normal life-style, while others are permanently hindered, often needing full time assistance.
Symptoms may be focal or limited to one region of the body, such as the neck or an arm or a leg. There are many different types of focal dystonia. Blepharospasm is marked by involuntary contraction of the muscles that control the movement of the eyelids. Symptoms may range from intermittent, painless, increased blinking to constant, painful, eye closure leading to functional blindness. In patients with cervical dystonia (CD), also known as spasmodic torticollis, muscle spasms of the head and neck may be painful and cause the neck to twist. These sometimes painful spasms may be intermittent or constant. Oromandibular and lingual dystonia is characterized by forceful contractions of the lower face causing the mouth to open or close. Chewing and unusual tongue movements may also occur. In spasmodic dysphonia (SD), also known as laryngeal dystonia, the muscles in the voice box (larynx) are affected. SD is marked by difficulties either opening or closing the vocal cords, causing the voice to have either a strained, hoarse, strangled, or whispering quality. In limb dystonia, there are involuntary contractions of one or more muscles in the arm, hand, leg, or foot. These types of focal dystonias include writer's cramp and other occupational dystonias.
Some patients have symptoms that are segmental or involve two adjacent areas of the body, such as the head and neck or arm and trunk. In other patients, symptoms may be multifocal or appear in two areas of the body that are not next to each other, such as the two arms, or an arm and a leg. In generalized dystonia, symptoms begin in an arm or a leg and advance, becoming more widespread. Eventually, the trunk and the rest of the body are involved.
Most cases of primary or idiopathic dystonia are believed to be hereditary and occur as the result of a faulty gene(s). In these patients, dystonia occurs as a solitary symptom and is not associated with an underlying disorder. For example, most cases of early-onset primary dystonia are due to a mutation in the DYT-1 gene. Early-onset dystonia that occurs as a result of this disease gene is the most common and severe type of hereditary dystonia. Other genetic causes of primary dystonia are rare.
Diseases involving dystonias include hereditary spastic paraplegia (HSP), a group of genetic, degenerative disorders of the spinal cord characterized by progressive weakness and stiffness of the legs; Huntington's disease (HD) a hereditary progressive neurodegenerative disorder characterized by the development of emotional, behavioral, and psychiatric abnormalities and movement abnormalities; multiple system atrophy (MSA) a neurodegenerative disease marked by a combination of symptoms affecting movement, blood pressure, and other body functions; pathologic myoclonus; progressive supranuclear palsy; restless legs syndrome; Rett syndrome; spasticity; Sydenham's chorea; Tourette syndrome; and Wilson disease.
Dystonia may occur because of another underlying disease process such as Wilson disease, multiple sclerosis, stroke, etc.; trauma to the brain, such as injury during a vehicular accident or anoxia during birth; or as a side effect of a medication. This type of dystonia is termed secondary or symptomatic dystonia. In adults, the most common type of secondary dystonia is tardive dystonia, which occurs as a result of the use of certain neuroleptic or antipsychotic drugs (used to treat psychiatric disorders). These drugs include haloperidol (Haldol®) or chlorpromazine (Thorazine®). Other drugs that block central dopamine receptors may also cause tardive dystonia. In most patients, symptoms occur some time after ongoing exposure to the drug. Table 1 provides a list of drugs that can cause dystonia.
TABLE 1Generic(Trade Names)Acetophenazine(Tindal ®)Amoxapine(Asendin ®)Chlorpromazine(Thorazine ®)Fluphenazine(Permitil ®, Prolixin ®)Haloperidol(Haldol ®)Loxapine(Loxitane ®, Daxolin ®)Mesoridazine(Serentil ®)Metaclopramide(Reglan ®)Molindone(Lindone ®, Moban ®)Perphenazine(Trilafon ® or Triavil ®)Piperacetazine(Quide ®)Prochlorperazine(Compazine ®, Combid ®)Promazine(Sparine ®)Promethazine(Phenergan ®)Thiethylperazine(Torecan ®)Thioridazine(Mellaril ®)Thiothixene(Navane ®)Trifluoperazine(Stelazine ®)Triflupromazine(Vesprin ®)Trimeprazine(Temaril ®)
There are a number of options available to treat dystonia. Drugs may be used alone or in combination. In addition, they may be combined with other forms of treatment. Drugs currently in use include botulinum toxin (BTX), benzodiazepines, Baclofen, anticholinergics and dopamine-blocking agents/dopamine-depleting agents. Surgical treatment is also available and includes thalamotomy, pallidotomy, deep brain stimulation, myectomy (myotomy), ramisectomy, rhizotomy and peripheral denervation.
Tardive Dyskinesia and Other Extrapyramidal Syndromes
The extrapyramidal system of the nervous system is centered on the basal ganglia and influences motor control through pyramidal pathways, generally by means of input to the thalamus. When the extrapyramidal system is disturbed, motor control is affected and patients suffer extrapyramidal syndromes. These are a combination of neurological effects that include tremors, chorea, athetosis, and dystonia. This is a common side effect of neuroleptic agents. Other medications known to cause these reactions include haloperidol, molindone, perphenazine and aminotriptyline, loxapine, pimozide, and rarely, benzodiazepines.
Tardive dyskinesia is an involuntary neurological movement disorder. Depending upon the type of onset, a differential diagnosis might include Sydenham's chorea, Huntington's chorea, congenital torsion dystonia, hysteria, and the stereotyped behavior or mannerism of schizophrenia. American College of Neuropsychopharmacology-FDA Task Force (1973). Tardive dyskinesia results from the use of neuroleptic drugs that are prescribed to treat certain psychiatric or gastrointestinal conditions. Long-term use of these drugs may produce biochemical abnormalities in the striatum. Tardive dystonia is believed to be the more severe form of tardive dyskinesia.
Other closely related, untreatable neurological disorders have now been recognized as variants of tardive dyskinesia. Tardive akathisia involves painful feelings of inner tension and anxiety and a compulsive drive to move the body. In the extreme, the individual undergoes internal torture and can no longer sit still. Tardive dystonia involves muscle spasms, frequently of the face, neck and shoulders, and it too can be disfiguring, disabling and agonizing.
Treatment of tardive dyskinesia has been unsatisfactory. Removal of the antipsychotic agent is often advocated (Baldessarini (1990)) but often results in more severe forms of the movement disorder. Various pharmaceutical agents have been tried with some reported success; early investigators in this area turned their attention to reserpine (Serpasil®), tradename of Ciba-Geigy a compound known to deplete dopamine levels. Reserpine and α-methyldopa (Aldomet®) in the treatment of long-standing tardive dyskinesia showed that both compounds were statistically more effective than placebo in reducing symptomatology. Huang et al. (1981). However, another study showed that, catecholamine synthesis blockers such as α-methyldopa have not demonstrated a beneficial effect on tardive dyskinesia. AMPT, an experimental agent that inhibits tyrosine hydroxylase, the rate-limiting step in the synthesis of dopamine and norepinephrine, has shown partial reduction of dyskinesia.
Formerly, tardive dyskinesia was often treated by increasing the dose of the neuroleptic. This initially treats the pathophysiology of tardive dyskinesia but can aggravate the pathogenesis by further denervation and subsequent hypersensitivity. Thus, the movements may decrease or disappear initially but then reappear later. The use of the atypical neuroleptic, clozapine may be useful in certain situations in which patients with disfiguring tardive dyskinesia need neuroleptic treatment alternative.
Lithium interferes with the presynaptic release of monoamines as well as having other actions on the CNS. Two studies report mild improvement in tardive dyskinesia with lithium while two others report no improvement or exacerbation. Tepper and Haas (1979).
Oral pimozide caused improvement in degree of movement. Clayeria et al. (1975). Buspirone (BuSpar®), a partial serotonin receptor agonist, may also be useful in treating the condition. Moss et al. (1993). In rats, buspirone reverses the DA receptor subsensitivity induced by chronic neuroleptic administration, and it is this effect that may also occur in humans due to partial agonist effects at D2 receptors. Reports have associated tardive dyskinesia with reserpine, tetrabenazine, metoclopramide, tricyclic antidepressants, benztropine, phenyloin and amphetamines.
Other than neuroleptics, the drug that regularly produces dyskinesia is L-DOPA and other dopaminergic agents, in patients receiving these drugs for Parkinson's diseases. L-DOPA actually can improve neuroleptic-induced tardive dyskinesia.
There is no accepted treatment for tardive dyskinesia. Casey (1999). Either discontinuing the offending antipsychotic or switching a patient to an atypical antipsychotic (with the possible exception of risperidone) may alleviate the movement disorder. The treatment of tardive dyskinesia has been recently reviewed. Egan et al. (1997). Most pharmacologic treatment strategies are directed toward reducing dopamine activity or enhancing CNS cholinergic effect. If the etiology of tardive dyskinesia relates to chronic dopaminergic receptor site blockade and the pathophysiology relates to the denervation hypersensitivity, agents that interrupt this sequence would, theoretically, be of potential benefit.
Many drugs have been tried in treating neuroleptic-induced tardive dyskinesia. Because of differences in patient populations, study design, and doses of agents used, the results for individual agents are conflicting. Baldessarini and Tarsy (1978); and Klawans et al. (1980).
Amine depleting agents e.g., reserpine and tetrabenazine, act by blocking the reuptake of dopamine, norepinephrine, and serotonin into the presynaptic neuronal storage vesicles, thereby depleting the brain of these substances. Studies with these agents have indicated improvement in tardive dyskinesia but side effects have limited their use and the studies are of short duration. Short-term suppression may occur as reported with neuroleptics.
Several cholinergic agonists have been administered to patients with tardive dyskinesia. Choline chloride and phosphatidylcholine (lecithin), which are orally bioavailable precursors of acetylcholine, have been reported to be useful in short-term studies. Deanol acetaminobenzoate was originally reported to be efficacious in the treatment of tardive dyskinesia, but other studies have not confirmed these findings. Gelenberg et al. (1990).
There have been several attempts to treat tardive dyskinesia with drugs believed to potentiate central GABA mechanisms. Thaker et al. (1990). In a study involving 10 patients with tardive dyskinesia of greater than a 6 month duration, benztropine 2 mg IV increased dyskinetic movements in 7 patients and reduced them in the remaining three. Moore and Bowers (1980). In a preliminary report the β-adrenergic blocking agent propranolol (Inderal®) in a dose of 30-60 mg/day produced marked resolution of tardive dyskinesia within 1 to 10 days of treatment in four patients. Wilbur and Kulik (1980).
Several studies have examined the effectiveness of treating tardive dyskinesia with vitamin E. Adler et al. (1999); Lohr and Caligiuri (1996); Lohr et al. (1988); Elkashef et al. (1990); Shriqui et al. (1992); Egan et al. (1992); Adler et al. (1993a); Adler et al. (1993b); Goldberg (1996); McCreadie et al. (1994); Dabiri et al. (1993); Bischot et al. (1993); Akhtar et al. (1993); and Dabiri et al. (1994).
It was previously thought that in the majority of patients, tardive dyskinesia is permanent or irreversible. However, this is not necessarily the case. The earlier tardive dyskinesia is diagnosed and the neuroleptic discontinued, the better the prognosis for disorder reversal. In young adults, tardive dyskinesia disappears within several weeks after early drug withdrawal. Uhrbrand and Faurbye (1960); Itoh et al. (1981); Driesens (1988); and Gardos et al. (1994).
Table 2 summarizes various agents that have been used to treat tardive dyskinesia.
TABLE 2Classes of AgentsSpecific agentsDopamine antagonistsButyrophenones, clozapine, metoclopramide (Karp etal. (1981)), papaverine (mechanism uncertain),phenothiazines, bromocriptine, pimozideDopamine D2 AgonistsBuspironeAmine-depleting agentsReserpine, tetrabenzineBlocker of catecholamineα-methyldopa, α-methyltyrosine (AMPT)synthesisCatecholamine releaseLithium saltsblockerCholinergic agentsDeanol, physostigmine, choline and lecithinGABA agonistsProgabide (Bartholini (1983)), valproic acid,baclofen, iazepam, clonazepamAnticholinergic agents.Benztropine, trihexyphenidylMoore et al. (1980)Agents with variable,α-methyldopa, amantadine, anticholinergicsnegligible, or uncertainantihistamines, apomorphine, barbiturates,effectsbenzodiazepines, methylphenidate, penicillamine,physostigmine, pyridoxine (B6), tryptophan, α-tocopherol(Vitamin E)Agents that worsen tardiveAnticholinergic agents, antiparkinson agents (e.g.,dyskinesiabenztropine), dopamine agonists, amphetamines,L-DOPANewer investigational agentsendopioids, Substance P, Cholecystokinin, Ceruletide,(peptides). Blurn et al.Neurotensin, Cyclo-Leucine-Glycine(1983)
Other motor syndromes caused by the effects of neuroleptic drugs on the extrapyramidal system include drug induced parkinsonism, akathisia, dystonia, oculogyric crisis, and opisthotonus. Akathisia is a condition that is characterized by motor restlessness, which may range from anxiety to an inability to lie or sit quietly, or to sleep, and possible causes include a toxic reaction to neuroleptics such as phenothiazine. An oculogyric crisis is the paroxysmal, involuntary upward deviation of the eyes. The eyelids are often retracted. Attacks last from a few minutes to a few hours. It may occur in patients sensitive to phenothiazines, haloperidol, and metoclopramide. Opisthotonus is a form of spasm in which head, neck and spine are arched backwards
Adenosine A2A Receptors
Adenosine is known to act via four major receptor subtypes, A1, A2A, A2B, A3, which have been characterized according to their primary sequences. Fredholm et al. (1994). Adenosine A2 receptors are further divided into A2A (high-affinity) and A2B (low-affinity) subtypes. Daly et al. (1983); and Burns et al. (1986). In contrast to the widespread distribution of A1, A2B, and A3 receptors in the brain, A2A receptors are highly localized to the basal ganglia, especially to the caudate-putamen (striatum), nucleus accumbens and globus pallidal, and the olfactory tubercles. Jarvis et al. (1989); and Schiffmann (1991b). The basal ganglia are located in the telencephalon and consist of several interconnected nuclei: the striatum, globus pallidus external segment (GPe), globus pallidus internal segment (GPi), substantia nigra pars compacta (SNc), substantia nigra pars reticulata (SNr), and subthalamic nucleus (STN). The basal ganglia are a critical component of subcortical circuits involved in the integration of sensorimotor, associative, and limbic information to produce motor behavior. A major component of basal ganglia is the striatum, where GABAergic medium spiny neurons, which represent more than 90% of striatal neuronal population, are the only projection neurons.
The medium spiny neurons receive massive glutamatergic inputs from the cortex and thalamus, and project their GABAergic output onto the major output nuclei of basal ganglia, i.e. GPi and SNr, via the striatopallidal medium spiny neurons in an “indirect pathway” and the striatonigral medium spiny neurons in a “direct pathway.” Alexander et al. (1990); Gerfen (1992); and Graybiel (1990). The medium spiny neurons also receive intrastriatal GABAergic, cholinergic, and nigrostriatal dopaminergic modulatory inputs. Neurons of the striatonigral direct pathway contain GABA plus substance P/dynorphin and directly project from the striatum to GPi/SNr. These neurons provide a direct inhibitory effect on GPi/SNr neurons. Striatal neurons in the striatopallidal indirect pathway contain GABA plus enkephalin and connect the striatum with the GPi/SNr via synaptic connections in the GPe and STN. In these neurons, A2A receptors are located almost exclusively on striatopallidal medium spiny neurons in the striatum and globus pallidus of the indirect pathway [Schiffmann et al. (1991a)], and acetylcholine-containing large aspiny interneurons in the striatum [Dixon et al. (1996)], and have been shown to modulate the neurotransmission of GABA, acetylcholine and glutamate. Kurokawa et al. (1996); Mori et al. (1996); Shindou et al. (2001); Ochi et al. (2000); Richardson et al. (1997); and Kase (2001).
Recent advances in neuroscience together with development of selective agents for the A2A receptors have contributed to increased knowledge about adenosine and the adenosine A2A receptor. Behavioral studies show that adenosine A2A receptor antagonists improve motor dysfunction of several parkinsonian animal models (e.g., MPTP-treated monkeys), but also reveal features of A2A receptor antagonists distinctive from dopaminergic agents. Richardson et al. (1997); Kase et al. (2000); and Kase (2001).
The antiparkinsonian effects of the selective adenosine A2A receptor antagonist KW-6002 have been studied in MPTP-treated marmosets and cynomologus monkeys. Kanda et al. (1998a); Grondin et al. (1999); and Kanda et al. (2000). In MPTP-treated marmosets, oral administration of KW-6002 induced an increase in locomotor activity lasting up to 11 hours in a dose-related manner. Kanda et al. (1998a). Locomotor activity was increased to the level observed in normal animals whereas L-DOPA induced locomotor hyperactivity. Furthermore, in L-DOPA-primed MPTP-treated marmosets, treatment with KW-6002 for 21 days induced little or no dyskinesias whereas under the same conditions, treatment with L-DOPA induced marked dyskinesias. When KW-6002 (20 mg/kg) was administered once a day for 5 days with a threshold dose of L-DOPA to MPTP-treated marmosets primed to exhibit dyskinesias, antiparkinson activity was potentiated without an increase in dyskinesia. Kanda et al. (2000). KW-6002 also additively increased the antiparkinsonian effect of quinpirole, a dopamine D2 receptor agonist but not SKF80723, a dopamine D1 receptor agonist. Taken together, these findings suggest that adenosine A2A antagonists might provide antiparkinsonian benefit as monotherapy in patients with early Parkinson's disease and might be able to improve antiparkinsonian response without increasing dyskinesia in L-DOPA-treated patients with motor complications.
Although the mechanisms by which adenosine A2A antagonists exert an antiparkinsonian effect remain to be fully elucidated, the following mechanism is now proposed.
In either Parkinson' s disease or MPTP treatment of primates, following destruction of the nigro-striatal dopaminergic pathway, the most relevant alteration is hyperactivity in the striatopallidal pathway, and such hyperactivity is attributed to an imbalance between the direct striatonigral pathway and the indirect striatopallidal pathway to give rise to parkinsonian state. DeLong (1990); and Obeso et al. (2000). It is noted that A2A receptors are specifically expressed on a subpopulation of medium spiny neurons, the striatopallidal medium spiny neurons but not the striatonigral medium spiny neurons.
The GABAergic striatopallidal medium spiny projection neuron was found as one of major target neurons of A2A receptor-mediated modulation. Kase (2001). Thus, in the striatum, A2A receptors control excitability of the projection neurons through the intrastriatal GABAergic feedback/feedforward inhibition network [Mori et al (1996)], and in the globus pallidus (GPe), A2A receptor activation enhances GABA release from the nerve terminals and might suppress excitability of GPe projection neurons, which project to subthalamus nucleus (STN) [Shindou et al. (2001)]. A2A receptor antagonists selectively block the dual modulation mechanism in the striatopallidal system, leading to suppression of the excessive activation in the striatopallidal medium spiny neurons. This might shift the striatopallidal/striatonigral neuronal imbalance towards the normal state, resulting in recovery of the motor function in parkinsonian state. Ochi et al (2000); Kase (2001), Aoyama et al (2002).
The action mechanism via A2A receptors could work independently of dopamine D2 receptors (Aoyama et al. (2000)), which are co-localized with A2A receptors in the striatopallidal medium spiny neurons. Gerfen et al. (1990). D2 receptor knockout mice (D2R−/−) presented a locomotor phenotype with analogies to Parkinson's disease and significantly altered in the levels of neuropeptide genes expressed in the striatal medium spiny neurons. No difference in the distribution and level of expression of A2A receptor mRNA and the binding properties of the receptor were found between D2R−/− and wild type mice, indicating that D2 receptor absence had no influence on A2A receptor properties. Blockade of A2A receptors by KW-6002 reestablished their locomotor activity and coordination of movement and lowered the levels of striatal enkephalin expression to those in normal mice. Aoyama et al. (2000). The results indicate that A2A and D2 receptors have antagonistic but independent activities in controlling neuronal and motor function in the basal ganglia. Independent functioning of A2A receptors from the dopaminergic system was confirmed by studies using A2A and D2 receptor knockout mice. Chen et al. (2001b).
Physiological and pathophysiological functions of A2A receptors in L-DOPA motor complications in Parkinson's disease are far from clear. Neuronal mechanisms of L-DOPA induced dyskinesia are generally thought to involve the indirect rather than the direct pathway. Crossman (1990). L-DOPA-induced dyskinesias arise when the activity in the STN or GPi falls below a given level as a consequence of excessive inhibition from the GPe. Obeso et al. (1997). Another hypothesis that abnormalities primarily in the direct pathway might contribute significantly to the genesis of L-DOPA-induced dyskinesia is proposed.
The neuroprotective effect of A2A receptor antagonists has been demonstrated in neurotoxin (MPTP or 6-hydroxydopamine)-induced dopaminergic neurodegeneration in rats and mice and A2A receptor knock-out mice. Ikeda et al. (2002); and Chen et al. (2001a). To date, no treatment has been successful in interfering with the basic pathogenic mechanism, which results in the death of dopaminergic neurons.
Therefore, non-dopaminergic drug therapies, which effect an adenosine A2A receptor blockade, offer a means to treat Parkinson's disease. Moreover, adenosine A2A receptor antagonists, which provide antiparkinsonian effects with little or no risk of typical dopaminergic drug adverse effects, i.e., increasing or developing motor complications, are desirable.
Some xanthine compounds are known to show adenosine A2A receptor antagonistic activity, anti-Parkinson's disease activity, antidepressant activity, inhibitory activity on neurodegeneration, or the like (U.S. Pat. Nos. 5,484,920; 5,587,378; and 5,543,415; EP 1016407A1; etc.)